The proposed work covered by this project relates to an investigation of the mechanisms by which hydroxylated phenothiazine metabolites inhibit ATP supported calcium accumulation and state III and state IV respiration in preparations of isolated rat brain mitochondria. It is desirable to determine how these actions differ from those of the parent compounds. The study includes an investigation of the structure- activity relationships of several phenothiazine analogs to their properties as mitochondrial inhibitors, an investigation of changes in the fine structure of isolated mitochondria as a result of treatment with hydroxylated phenothiazines and an attempt to characterize the interaction of hydroxylated phenothiazines with mitochondrial sites during calcium accumulation and during respiration. Since it is known that oxidative metabolism and intraneuronal calcium regulation are essential for the maintenance of neuronal activity, the effects of hydroxylated phenothiazine metabolites on mitochondria may be of some importance in the therapeutic or toxic effects of chlorpromazine.